Project Summary Although antiretroviral therapy prolongs life, it does not fully restore health. For reasons that remain controversial, HIV-infecte individuals doing well on therapy have a shortened lifespan as compared to their uninfected counterparts and also have a higher than expected risk of a number of non-AIDS conditions including cardiovascular disease. HIV-infected individuals have a 2-fold higher risk of myocardial infarction and higher rates of sudden cardiac death. While the underlying mechanism for these clinical observations is likely multifactorial, chronic inflammation in the setting of treated HIV infection has emerged as a key contributor to the disease process. IL-1? is a pro-inflammatory cytokine produced by monocytes, macrophages and dendritic cells; IL-1? inhibition using canakinumab, a monoclonal antibody to IL-1?, dramatically reduces inflammatory markers, and has been studied in > 8500 individuals without HIV in the CANTOS study. In order to determine the impact of IL-1? inhibition on systemic inflammation during long-term antiretroviral-treated HIV infection, we propose to perform a single center pathogenesis-oriented study assessing the impact of canakinumab-a human monoclonal antibody which inhibits IL-1?-on systemic inflammation, T cell activation, and vascular inflammation. Given the putative role that inflammation has in contributing to viral persistence, we will also measure the impact of canakinumab on the size of the HIV reservoir. We will perform a randomized double-blinded placebo-controlled proof-of-concept clinical trial evaluating the safety and effects of canakinumab administered to long-term antiretroviral treated patients who have undetectable HIV RNA levels. We propose the following aims: Aim 1: To determine the safety, tolerability, and pharmacokinetics of IL-1? inhibition using canakinumab in effectively treated and suppressed HIV infected adults. We will perform an initial pilot study in ten individuals who will all receivea single dose of canakinumab; if the drug is safe and well tolerated (as expected), we will enroll 100 additional individuals in a randomized, placebo controlled trial under Aims 1-3; Aim 2: To demonstrate that IL-1? inhibition decreases inflammatory markers and monocyte activation, and improves vascular inflammation and endothelial dysfunction among treated and suppressed HIV-infected individuals; Aim 3: To determine whether IL-1? inhibition reduces T cell activation and decreases the size of the HIV reservoir in blood. This application combines (1) a dedicated and successful multidisciplinary team with a strong record of collaboration, (2) the ability to rapidly recruit subjects from existing cohorts of HIV-infected subjects, (3) the collaboration of senior investigators performing innovative immunology assays and measurements of HIV persistence.